Modulators of programmed death-ligand-1 and/or programmed death-ligand-2

ABSTRACT

The present disclosure is concerned with dipeptide compounds for the treatment of various cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 62/943,728,filed on Dec. 4, 2019, the contents of which are hereby incorporated byreference in their entirety.

BACKGROUND

Programmed Cell Death-1 (PD-1) is a cell surface protein important inthe regulation of the immune system, specifically involving T-cells,which promote immune tolerance to self-antigens. The interaction betweenthis surface receptor and its predominant ligand, 1 (PDL-1), has emergedas a prime therapeutic target for overcoming the tumor survivalmechanism known as immune evasion. A critical barrier to therapeuticsuccess with large biologics, such as checkpoint antibodies, is that theefficacy in solid tumors is limited, partially due to poor tumorpenetrance, and the solution to this lies within the adaptability ofsmall molecule design. Expression of PDL-1 on cells within the tumormicroenvironment, thereby engaging the PD-1 checkpoint pathway, maskscancerous cells to the tumor infiltrating CD8⁺cytotoxic T-lymphocytes(CTLs). This is significant in that CTLs are rendered inactive towardscancerous cells, subsequently triggering exhaustion, and eventual celldeath. Moreover, high PDL-1 expression on tumor cells is linked to poorprognosis, and is an indicator of tumor-induced immune evasion. It hasbeen demonstrated that intravenous (i.v.) administration of anantibody-based checkpoint inhibitor is sufficient to disrupt thisdownregulating checkpoint interaction, negating the effect of PDL-1expression, and restoring CTL anti-tumor activity. Specifically, the useof therapeutic antibodies against PD-1 have been reported to have aresponse rate of 19% in patients with advanced triple negative breastcancer when the tumor expresses PDL-1, and a 46% response rate whenprovided as combination therapy with paclitaxel, a chemotherapeuticagent, in patients who do not have high levels of PDL-1. However, suchantibody therapies, while showing some efficacy in metastatic disease,have several disadvantages, including adverse side effects (e.g.,colitis, endocrinopathies, and inflammatory arthritis), high dosagerequirements, and the need for intravenous administration. Thus, thereremains a need for compounds and compositions for modulating PDL-1 andmethods of making and using same in the treatment of, for example,cancer.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds and compositions for use in the prevention and treatment ofdisorders of uncontrolled cellular proliferation such as, for example,cancers including, but not limited to, sarcomas, carcinomas,hematological cancers, solid tumors, breast cancer, cervical cancer,gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer,prostate cancer, ovarian cancer, bladder cancer, thyroid cancer,testicular cancer, pancreatic cancer, endometrial cancer, melanomas,gliomas, leukemias, lymphomas, chronic myeloproliferative disorders,myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cellneoplasms (myelomas).

Thus, disclosed are compounds having a structure represented by aformula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C1-C4 alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C1-C4 alkyl; wherein R³ is selected from —(C1-C8alkyl)NR^(10a)R^(10b), —(C1-C8 alkyl)C(O)NR^(10a)R^(10b), C2-C8 alkyl,and —(C1-C4)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C1-C4 alkyl; wherein Ar² is C6 arylpara-substituted with a —(CH₂)_(m) NR^(20a)R^(20b) group, andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; wherein m is 1, 2, 3, or 4; and wherein each of R^(20a) andR^(20b) is independently selected from hydrogen and C1-C4 alkyl; whereineach of R^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) _(an)dR^(5b) is independently C1-C4 alkyl; or wherein each of R^(5a) andR^(5b) are covalently bonded and, together with the intermediate atoms,comprise an unsubstituted C3-C6 group; and wherein R⁶ is hydrogen; orwherein each of R^(5a) and R^(5b) together are covalently bonded to R⁶and, together with the intermediate atoms, comprise a C3-C5 heteroarylgroup substituted 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl; and wherein Ar¹ is selected from aryl and heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, or a pharmaceutically acceptable salt thereof, provided thatwhen each of R^(5a) and R^(5b) is hydrogen, then R³ is not C2-C8 alkyl,and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C1-C4 alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C3-C6 group, and R⁶ is hydrogen.

Also disclosed are methods for making a disclosed compound.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are methods for treating a disorder of uncontrolledcellular proliferation in a subject, the method comprising administeringto the subject an effective amount of a disclosed compound, therebytreating the disorder.

Also disclosed are methods for modifying programmed death-ligand-1(PDL-1) and/or programmed death-ligand-2 (PDL-2) signaling in a subject,the method comprising administering to the subject an effective amountof a disclosed compound, thereby modifying PDL-1 and/or PDL-2 signalingin the subject.

Also disclosed are methods for modifying PDL-1 and/or PDL-2 signaling ina cell, the method comprising contacting the cell with an effectiveamount of a disclosed compound, thereby modifying PDL-1 and/or PDL-2signaling in the cell.

Also disclosed are kits comprising a disclosed compound, and one or moreof: more of: (a) at least one agent associated with the treatment of adisorder of uncontrolled cellular proliferation; (b) instructions foradministering the compound in connection with treating a disorder ofuncontrolled cellular proliferation; and (c) instructions for treating adisorder of uncontrolled cellular proliferation.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a representative NMR-resolved co-structure of theextracellular domain of PD1 with compound no. 4.

FIG. 2 shows representative docking simulations of the PD-1 portion ofPDB ID 4ZQK with compound no. 4.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated ±10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half-maximal (50%) inhibitoryconcentration (IC) of a substance.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an ECso canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage forms can comprise inventive a disclosed compound, aproduct of a disclosed method of making, or a salt, solvate, orpolymorph thereof, in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14th edition), thePhysicians' Desk Reference (64th edition), and The Pharmacological Basisof Therapeutics (12th edition), and they include, without limitation,medicaments; vitamins; mineral supplements; substances used for thetreatment, prevention, diagnosis, cure or mitigation of a disease orillness; substances that affect the structure or function of the body,or pro-drugs, which become biologically active or more active after theyhave been placed in a physiological environment. For example, the term“therapeutic agent” includes compounds or compositions for use in all ofthe major therapeutic areas including, but not limited to, adjuvants;anti-infectives such as antibiotics and antiviral agents; anti-cancerand anti-neoplastic agents such as kinase inhibitors, poly ADP ribosepolymerase (PARP) inhibitors and other DNA damage response modifiers,epigenetic agents such as bromodomain and extra-terminal (BET)inhibitors, histone deacetylase (HDAc) inhibitors, iron chelotors andother ribonucleotides reductase inhibitors, proteasome inhibitors andNedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin(mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox,irinotecan, and platinum compounds, immune checkpoint blockade agentssuch as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody(mAB), programmed cell death protein 1 (PD-1)/programmed celldeath-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB,toll-like receptor (TLR) agonists and other immune modifiers, celltherapeutics such as chimeric antigen receptor T-cell (CAR-T)/chimericantigen receptor natural killer (CAR-NK) cells, and proteins such asinterferons (IFNs), interleukins (ILs), and mAbs; anti-ALS agents suchas entry inhibitors, fusion inhibitors, non-nucleoside reversetranscriptase inhibitors (NNRTIs), nucleoside reverse transcriptaseinhibitors (NRTIs), nucleotide reverse transcriptase inhibitors, NCP7inhibitors, protease inhibitors, and integrase inhibitors; analgesicsand analgesic combinations, anorexics, anti-inflammatory agents,anti-epileptics, local and general anesthetics, hypnotics, sedatives,antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics,antagonists, neuron blocking agents, anticholinergic and cholinomimeticagents, antimuscarinic and muscarinic agents, antiadrenergics,antiarrhythmics, antihypertensive agents, hormones, and nutrients,antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines,antinauseants, antineoplastics, antipruritics, antipyretics;antispasmodics, cardiovascular preparations (including calcium channelblockers, beta-blockers, beta-agonists and antiarrythmics),antihypertensives, diuretics, vasodilators; central nervous systemstimulants; cough and cold preparations; decongestants; diagnostics;hormones; bone growth stimulants and bone resorption inhibitors;immunosuppressives; muscle relaxants; psychostimulants; sedatives;tranquilizers; proteins, peptides, and fragments thereof (whethernaturally occurring, chemically synthesized or recombinantly produced);and nucleic acid molecules (polymeric forms of two or more nucleotides,either ribonucleotides (RNA) or deoxyribonucleotides (DNA) includingboth double- and single-stranded molecules, gene constructs, expressionvectors, antisense molecules and the like), small molecules (e.g.,doxorubicin) and other biologically active macromolecules such as, forexample, proteins and enzymes. The agent may be a biologically activeagent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they havebeen placed in a predetermined physiological environment.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)-, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹—(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4π+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula—(A¹O(O)C-A²-C(O)O)_(a)- or —(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula —(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, C1, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, 0, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclicheterocycle.” Heterocycle includes pyridine, pyrimidine, furan,thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole,imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole,1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including,1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazoleand 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂₀A¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “Re,” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o)C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o) ₂;—(CH₂)₀₋₄N(R^(o)C(O)OR^(o); —N(R^(o)N(R^(o)C(O)R^(o);)—N(R^(o)N(R^(o)C(O)NR^(o) ₂; —N(R^(o)N(R^(o)C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄ C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄ SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —(CH₂)₀₋₄ OC(O)NR^(o)₂; —C(O)N(OR^(o)R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o)R^(o); —(CH₂)₀₋₄ SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂; —(CH₂)₀₋₄S(O)R^(o); —N(R^(o)S(O)₂NR^(o) ₂; —N(R^(o)S(O)₂R^(o); —N(OR^(o)R^(o);—C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o) ₂; —OP(O)(OR^(o)₂; SiR^(o) ₃; —(C₁₋₄ straight or branched)alkylene)O—N(R^(o) ₂; or—(C₁₋₄ straight or branched)alkylene)C(O)O—N(R^(o) ₂, wherein each R^(o)may be substituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), ora 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂ R^(⋅), -(haloR^(⋅)),—(CH₂)₀₋₂ OH, —(CH₂)₀₋₂ OR^(⋅), —(CH₂)₀₋₂ CH(OR^(⋅))₂; —O(haloR^(⋅)),—CN, —N₃, —(CH₂)₀₋₂C(O)R^(⋅), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(⋅),—(CH₂)₀₋₂ SR^(⋅), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂ NH₂, —(CH₂)₀₋₂ NHR^(⋅),—(CH₂)₀₋₂ NR^(⋅) ₂, —NO₂, —SiR^(⋅) ₃, —SiR^(⋅) ₃, —C(O)SR^(⋅), —(C₁₋₄straight or branched alkylene)C(O)OR^(⋅), or —SSR^(⋅) wherein each R^(⋅)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(⋅), -(haloR^(⋅)), —OH, —OR^(⋅), —O(haloR^(⋅), —CN, —C(O)OH,—C(O)OR^(⋅), —NH₂, —NHR^(⋅), —NR^(⋅) ₂, or —NO₂, wherein each R^(⋅) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(⋅), -(haloR^(⋅), —OH, —OR^(⋅), —O(haloR^(⋅), —CN, —C(O)OH,—C(O)OR^(⋅), —NH₂, —NHR^(⋅), —NR^(⋅) ₂, or —NO₂, wherein each R^(⋅) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

When the disclosed compounds contain one chiral center, the compoundsexist in two enantiomeric forms. Unless specifically stated to thecontrary, a disclosed compound includes both enantiomers and mixtures ofenantiomers, such as the specific 50:50 mixture referred to as a racemicmixture. The enantiomers can be resolved by methods known to thoseskilled in the art, such as formation of diastereoisomeric salts whichmay be separated, for example, by crystallization (see, CRC Handbook ofOptical Resolutions via Diastereomeric Salt Formation by David Kozma(CRC Press, 2001)); formation of diastereoisomeric derivatives orcomplexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step can liberate the desired enantiomeric form. Alternatively,specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designatedenantiomeric form of the compounds can be provided in enantiomericexcess (e.e.). Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%, for example, greater than60%, greater than 70%, greater than 75%, greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 98%, or greaterthan 99%. In one aspect, the designated enantiomer is substantially freefrom the other enantiomer. For example, the “R” forms of the compoundscan be substantially free from the “S” forms of the compounds and are,thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms ofthe compounds can be substantially free of “R” forms of the compoundsand are, thus, in enantiomeric excess of the “R” forms.

When a disclosed compound has two or more chiral carbons, it can havemore than two optical isomers and can exist in diastereoisomeric forms.For example, when there are two chiral carbons, the compound can have upto four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and(R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirrorimage stereoisomers of one another. The stereoisomers that are notmirror-images (e.g., (S,S) and (R,S)) are diastereomers. Thediastereoisomeric pairs can be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Unless otherwise specifically excluded, a disclosedcompound includes each diastereoisomer of such compounds and mixturesthereof.

The compounds according to this disclosure may form prodrugs at hydroxylor amino functionalities using alkoxy, amino acids, etc., groups as theprodrug forming moieties. For instance, the hydroxymethyl position mayform mono-, di- or triphosphates and again these phosphates can formprodrugs. Preparations of such prodrug derivatives are discussed invarious literature sources (examples are: Alexander et al., J. Med.Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).The nitrogen function converted in preparing these derivatives is one(or more) of the nitrogen atoms of a compound of the disclosure.

“Derivatives” of the compounds disclosed herein are pharmaceuticallyacceptable salts, prodrugs, deuterated forms, radio-actively labeledforms, isomers, solvates and combinations thereof. The “combinations”mentioned in this context are refer to derivatives falling within atleast two of the groups: pharmaceutically acceptable salts, prodrugs,deuterated forms, radio-actively labeled forms, isomers, and solvates.Examples of radio-actively labeled forms include compounds labeled withtritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and thelike.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R″ is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Strem Chemicals (Newburyport, Mass.),Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40(John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (JohnWiley and Sons, 4th Edition); and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compounds and compositions disclosed hereinhave certain functions. Disclosed herein are certain structuralrequirements for performing the disclosed functions, and it isunderstood that there are a variety of structures that can perform thesame function that are related to the disclosed structures, and thatthese structures will typically achieve the same result.

B. Dipeptides

In one aspect, the invention relates to dipeptides useful in treatingdisorders associated with a disorder of uncontrolled cellularproliferation such as, for example, cancers including, but not limitedto, sarcomas, carcinomas, hematological cancers, solid tumors, breastcancer, cervical cancer, gastrointestinal cancer, colorectal cancer,brain cancer, skin cancer, prostate cancer, ovarian cancer, bladdercancer, thyroid cancer, testicular cancer, pancreatic cancer,endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronicmyeloproliferative disorders, myelodysplastic syndromes,myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).

In one aspect, the compounds of the invention are useful in thetreatment of disorders of uncontrolled cellular proliferation, asfurther described herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁-C₈ alkyl)C(O)NR^(10a)-R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and -R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Are is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, provided that atleast two of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) arehydrogen.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound is selected from:

In one aspect, n is 0 or 1. In a further aspect, n is 0. In a stillfurther aspect, n is 1.

In one aspect, m is 1, 2, 3, or 4. In a further aspect, m is 1, 2, or 3.In a still further aspect, m is 1 or 2. In yet a further aspect, m is 2or 3. In an even further aspect, m is 3 or 4. In a still further aspect,m is 4. In yet a further aspect, m is 3. In an even further aspect, m is2. In a still further aspect, m is 1.

a. R^(1a) and R^(1b) Groups

In one aspect, each of R^(1a) and R^(1b), when present, is independentlyselected from hydrogen, halogen, and C₁-C₄ alkyl; or each of R^(1a) andR^(1b), when present, are covalently bonded and, together with theintermediate atoms, comprise an unsubstituted cyclopropyl group.

Thus, in one aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl. In afurther aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, —F, —C₁, —Br, methyl, ethyl,n-propyl, and isopropyl. In a still further aspect, each of R^(1a) andR^(1b), when present, is independently selected from hydrogen, —F, —C₁,methyl, and ethyl. In yet a further aspect, each of R^(1a) and R^(1b),when present, is independently selected from hydrogen, —F, —C₁, andmethyl.

In a further aspect, each of R^(1a) and R^(1b), when present, ishydrogen.

In a further aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen and halogen. In a still furtheraspect, each of R^(1a) and R^(1b), when present, is independentlyselected from hydrogen, —F, —C₁, and —Br. In yet a further aspect, eachof R^(1a) and R^(1b), when present, is independently selected fromhydrogen, —F, and —C₁. In an even further aspect, each of R^(1a) andR^(1b), when present, is independently selected from hydrogen and —F.

In a further aspect, each of R^(1a) and R^(1b), when present, isindependently halogen. In a still further aspect, each of R^(1a) andR^(1b), when present, is independently selected from —F, —C₁, and —Br.In yet a further aspect, each of R^(1a) and R^(1b), when present, isindependently selected from —F and —C₁. In an even further aspect, eachof R^(1a) and R^(1b), when present, is —F.

In a further aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen and C₁-C₄ alkyl. In a furtheraspect, each of R^(1a) and R^(1b), when present, is independentlyselected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In astill further aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, methyl, and ethyl. In yet afurther aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen and methyl.

In a further aspect, each of R^(1a) and R^(1b), when present, isindependently C₁-C₄ alkyl. In a further aspect, each of R^(1a) andR^(1b), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In a still further aspect, each of R^(1a) andR^(1b), when present, is independently selected from methyl and ethyl.In yet a further aspect, each of R^(1a) and R^(1b), when present, ismethyl.

In one aspect, each of R^(1a) and R^(1b), when present, are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted cyclopropyl group.

b. R² and R⁴ Groups

In one aspect, each of R² and R⁴ is independently selected from hydrogenand C₁-C₄ alkyl. In a further aspect, each of R² and R⁴ is independentlyselected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In astill further aspect, each of R² and R⁴ is independently selected fromhydrogen, methyl, and ethyl. In yet a further aspect, each of R² and R⁴is independently selected from hydrogen and ethyl. In an even furtheraspect, each of R² and R⁴ is independently selected from hydrogen andmethyl.

In a further aspect, each of R² and R⁴ is hydrogen.

c. R³ Groups

In one aspect, R³ is selected from —(C₁-C₈ alkyl)NR^(10a)R^(10b),—(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl, and —(C₁-C₄)Ar². In afurther aspect, R³ is selected from —(C₁-C₄ alkyl)NR^(10a)R^(10b),—(C₁-C₄ alkyl)C(O)NR^(10a)R^(10b), C₂-C₄ alkyl, and —(C₁-C₄)Ar². In astill further aspect, R³ is selected from —CH₂NR^(10a)R^(10b),—CH₂CH₂NR^(10a)R^(10b), —CH₂CH₂CH₂NR^(10a)R^(10b),—CH(CH₃)CH₂NR^(10a)R^(10b), —CH₂C(O)NR^(10a)R^(10b),—CH₂CH₂C(O)NR^(10a)R^(10b), —CH₂CH₂CH₂C(O)NR^(10a)R^(10b),—CH(CH₃)CH₂C(O)_(NR) ^(10a) R^(10b), ethyl, n-propyl, isopropyl,—CH₂Ar², —CH₂CH₂Ar², —CH₂CH₂CH₂Ar², and —CH(CH₃)CH₂Ar². In yet a furtheraspect, R³ is selected from —CH₂NR^(10a) R^(10b),—CH₂CH₂NR^(10a)R^(10b), —CH₂C(O)NR^(10a)R^(10b),—CH₂CH₂C(O)NR^(10a)R^(10b), ethyl, —CH₂Ar², and —CH₂CH₂Ar². In an evenfurther aspect, R³ is selected from —CH₂NR^(10a)R^(10b),—CH₂C(O)NR^(10a)R^(10b), and —CH₂Ar².

In various aspects, R³ is selected from —(C₁-C₈ alkyl)NR^(10a)R^(10b)and —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b). In a further aspect, R³ isselected from —(C₁-C₄ alkyl)NR^(10a)R^(10b) and —(C₁-C₄alkyl)C(O)NR^(10a)R^(10b). In a still further aspect, R³ is selectedfrom —CH₂NR^(10a)R^(10b), —CH₂CH₂NR^(10a)R^(10b),—CH₂CH₂CH₂NR^(10a)R^(10b), —CH(CH₃)CH₂NR^(10a)R^(10b),—CH₂C(O)NR^(10a)R^(10b), —CH₂CH₂C(O)NR^(10a)R^(10b), —CH₂CH₂CH₂C(O)_(NR)^(10a)R^(10b), and —CH(CH₃)CH₂C(O)NR^(10a)R^(10b). In yet a furtheraspect, R³ is selected from —CH₂NR^(10a)R^(10b), —CH₂CH₂NR^(10a)R^(10b),—CH₂C(O)NR^(10a)R^(10b), and —CH₂CH₂C(O)NR^(10a)R^(10b). In an evenfurther aspect, R³ is selected from —CH₂NR^(10a)R^(10b) and—CH₂C(O)NR^(10a)R^(10b).

In various aspects, R³ is —(C₁-C₈ alkyl)NR^(10a)R^(10b). In a furtheraspect, R³ is —(C₁-C₄ alkyl)NR^(10a)R^(10b). In a still further aspect,R³ is selected from —CH₂NR^(10a)R^(10b), —CH₂CH₂NR^(10a)R^(10b),—CH₂CH₂CH₂NR^(10a)R^(10b), and —CH(CH₃)CH₂NR^(10a)R^(10b). In yet afurther aspect, R³ is selected from —CH₂NR^(10a)R^(10b) and—CH₂CH₂NR^(10a)R^(10b). In an even further aspect, R³ is—CH₂NR^(10a)R^(10b).

In various aspects, R³ is —(C₁-C₈ alkyl)NH₂. In a further aspect, R³ is—(C₁-C₄ alkyl)NH₂. In a still further aspect, R³ is selected from—CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In yet a furtheraspect, R³ is selected from —CH₂NH₂ and —CH₂CH₂NH₂. In an even furtheraspect, R³ is —CH₂NH₂.

In a further aspect, R³ is —(C₃-C₄ alkyl)NR^(10a)R^(10b). In a stillfurther aspect, R³ is —(C₃-C₄ alkyl)NH₂.

In various aspects, R³ is —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b). In afurther aspect, R³ is —(C₁-C₄ alkyl)C(O)NR^(10a)R^(10b). In a stillfurther aspect, R³ is selected from —CH₂C(O)NR^(10a)R^(10b),—CH₂CH₂C(O)NR^(10a)R^(10b), —CH₂CH₂CH₂C(O)NR^(10a)R^(10b), and—CH(CH₃)CH₂C(O)NR^(10a)R^(10b). In yet a further aspect, R³ is selectedfrom —CH₂C(O)NR^(10a)R^(10b) and —CH₂CH₂C(O)NR^(10a)R^(10b). In an evenfurther aspect, R³ is —CH₂C(O)NR^(10a)R^(10b).

In various aspects, R³ is —(C₁-C₈ alkyl)C(O)NH₂. In a further aspect, R³is —(C₁-C₄ alkyl)C(O)NH₂. In a still further aspect, R³ is selected from—CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂C(O)NH₂, and —CH(CH₃)CH₂C(O)NH₂.In yet a further aspect, R³ is selected from —CH₂C(O)NH₂ and—CH₂CH₂C(O)NH₂. In an even further aspect, R³ is —CH₂C(O)NH₂.

In various aspects, R³ is selected from C₂-C₈ alkyl and —(C₁-C₄)Ar². Ina further aspect, R³ is selected from C₂-C₄ alkyl and —(C₁-C₄)Ar². In astill further aspect, R³ is selected from ethyl, n-propyl, isopropyl,—CH₂Ar², —CH₂CH₂Ar², —CH₂CH₂CH₂Ar², and —CH(CH₃)CH₂Ar². In yet a furtheraspect, R³ is selected from ethyl —CH₂Ar², and —CH₂CH₂Ar².

In various aspects, R³ is C₂-C₈ alkyl. In a further aspect, R³ is C₂-C₄alkyl. In a still further aspect, R³ is selected from ethyl, n-propyl,and isopropyl. In yet a further aspect, R³ is ethyl.

In a further aspect, R³ is C₄ alkyl. In a still further aspect, R³ isselected from n-butyl, isobutyl, and sec-butyl. In a still furtheraspect, R³ is selected from n-butyl and isobutyl. In yet a furtheraspect, R³ is n-butyl.

In various aspects, R³ is —(C₁-C₄)Ar². In a further aspect, R³ is—(C₁-C₄)Ar². In a still further aspect, R³ is selected from —CH₂Ar²,—CH₂CH₂Ar², —CH₂CH₂CH₂Ar², and —CH(CH₃)CH₂Ar². In yet a further aspect,R³ is selected from —CH₂Ar² and —CH₂CH₂Ar². In an even further aspect,R³ is —CH₂Ar².

In a further aspect, R³ is a structure:

d. R^(5a), R^(5b), and R⁶ Groups

In one aspect, each of R^(5a) and R^(5b) is hydrogen; or each of R^(5a)and R^(5b) is independently C₁-C₄ alkyl; or each of R^(5a) and R^(5b)are covalently bonded and, together with the intermediate atoms,comprise an unsubstituted C₃-C₆ group; and R⁶ is hydrogen; or each ofR^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl.

Thus, in one aspect, each of R^(5a), R^(5b), and R⁶ is hydrogen.

In one aspect, each of R^(5a) and R^(5b) is independently C₁-C₄ alkyland R⁶ is hydrogen. In a further aspect, each of R^(5a) and R^(5b) isindependently selected from methyl, ethyl, n-propyl, and isopropyl. In astill further aspect, each of R^(5a) and R^(5b) is independentlyselected from methyl and ethyl. In yet a further aspect, each of R^(5a)and R^(5b) is ethyl. In an even further aspect, each of R^(5a) andR^(5b) is methyl.

In one aspect, each of R^(5a) and R^(5b) are covalently bonded and,together with the intermediate atoms, comprise an unsubstituted C₃-C₆group and R⁶ is hydrogen. In a further aspect, each of R^(5a) and R^(5b)are covalently bonded and, together with the intermediate atoms,comprise an unsubstituted C₃-C₅ group. In a still further aspect, eachof R^(5a) and R^(5b) are covalently bonded and, together with theintermediate atoms, comprise an unsubstituted C₃-C₄ group. In yet afurther aspect, each of R^(5a) and R^(5b) are covalently bonded and,together with the intermediate atoms, comprise an unsubstitutedcyclohexyl group. In an even further aspect, each of R^(5a) and R^(5b)are covalently bonded and, together with the intermediate atoms,comprise an unsubstituted cyclopentyl group. In a still further aspect,each of R^(5a) and R^(5b) are covalently bonded and, together with theintermediate atoms, comprise an unsubstituted cyclobutyl group. In yet afurther aspect, each of R^(5a) and R^(5b) are covalently bonded and,together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group.

In one aspect, each of R^(5a) and R^(5b) together are covalently bondedto R⁶ and, together with the intermediate atoms, comprise a C₃-C₅heteroaryl group substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a further aspect, each of R^(5a) and R^(5b) together arecovalently bonded to R⁶ and, together with the intermediate atoms,comprise a C₃-C₅ heteroaryl group substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, each ofR^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted with 0 or 1 group selected from halogen, —CN, —NH₂, —OH,—NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl,C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet a furtheraspect, each of R^(5a) and R^(5b) together are covalently bonded to R⁶and, together with the intermediate atoms, comprise a C₃-C₅ heteroarylgroup monosubstituted with a group selected from halogen, —CN, —NH₂,—OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In aneven further aspect, each of R^(5a) and R^(5b) together are covalentlybonded to R⁶ and, together with the intermediate atoms, comprise anunsubstituted with C₃-C₅ heteroaryl group.

In various aspects, each of R^(5a) and R^(5b) together are covalentlybonded to R⁶ and, together with the intermediate atoms, comprise apyridin-2(1H)-onyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a further aspect, each of R^(5a) and R^(5b) together arecovalently bonded to R⁶ and, together with the intermediate atoms,comprise a pyridin-2(1H)-onyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, each ofR^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a pyridin-2(1H)-onyl substitutedwith 0 or 1 group selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet a furtheraspect, each of R^(5a) and R^(5b) together are covalently bonded to R⁶and, together with the intermediate atoms, comprise a pyridin-2(1H)-onylmonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl,C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In an even furtheraspect, each of R^(5a) and R^(5b) together are covalently bonded to R⁶and, together with the intermediate atoms, comprise an unsubstitutedwith pyridin-2(1H)-onyl.

In a further aspect, each of R^(5a) and R^(5b) together are covalentlybonded to R⁶ and, together with the intermediate atoms, comprise astructure:

e. R^(10a) and R^(10b) Groups

In one aspect, each of R^(10a) and R^(10b) is independently selectedfrom hydrogen and C₁-C₄ alkyl. In a further aspect, each of R^(10a) andR^(10b) is independently selected from hydrogen, methyl, ethyl,n-propyl, and isopropyl. In a still further aspect, each of R^(10a) andR^(10b) is independently selected from hydrogen, methyl, and ethyl. Inyet a further aspect, each of R^(10a) and R^(10b) is independentlyselected from hydrogen and ethyl. In an even further aspect, each ofR^(10a) and R^(10b) is independently selected from hydrogen and methyl.

In a further aspect, each of R^(10a) and R^(10b) is hydrogen.

In various aspects, each of R^(10a) and R^(10b) is independently C₁-C₄alkyl. In a further aspect, each of R^(10a) and R^(10b) is independentlyselected from methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, each of R^(10a) and R^(10b) is independently selected frommethyl and ethyl. In yet a further aspect, each of R^(10a) and R^(10b)is ethyl. In an even further aspect, each of R^(10a) and R^(10b) ismethyl.

f. R^(20a) and R^(20b) Groups

In one aspect, each of R^(20a) and R^(20b) is independently selectedfrom hydrogen and C₁-C₄ alkyl. In a further aspect, each of R^(20a) andR^(20b) is independently selected from hydrogen, methyl, ethyl,n-propyl, and isopropyl. In a still further aspect, each of R^(20a) andR^(20b) is independently selected from hydrogen, methyl, and ethyl. Inyet a further aspect, each of R^(20a) and R^(20b) is independentlyselected from hydrogen and ethyl. In an even further aspect, each ofR^(n)a and R^(20b) is independently selected from hydrogen and methyl.

In a further aspect, each of R^(20a) and R^(20b) is hydrogen.

In various aspects, each of R^(20a) and R^(20b) is independently C₁-C₄alkyl. In a further aspect, each of R^(20a) and R^(20b) is independentlyselected from methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, each of R^(20a) and R^(20b) is independently selected frommethyl and ethyl. In yet a further aspect, each of R^(20a) and R^(20b)is ethyl. In an even further aspect, each of R^(20a) and R^(20b) ismethyl.

g. R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) Groups

In one aspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e)are independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, provided that atleast two of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) arehydrogen. In a further aspect, each of R^(21a), R^(21b), R^(21c),R^(21d), and R^(21e) are independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, methyl, ethyl, n-propyl, isopropyl, ethenyl,n-propenyl, isopropenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F,—CH(CH₃)CH₂F, —CH₂C₁, —CHCl₂, —CCl₃, —CH₂CH₂C₁, —CH₂CH₂CH₂C₁,—CH(CH₃)CH₂C₁, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCH₂F, —OCHF2, —OCF₃,—OCH2CH₂F, —OCH2CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH3, —OCH2CH₃, —OCH2CH₂CH₃,—OCH(CH₃)₂, —NHCH3, —NHCH2CH₃, —NHCH2CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)₂)₂, —CH₂NH₂,—CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), are independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, ethyl,ethenyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂C₁, —CHCl₂, —CCl₃, —CH₂CH₂C₁,—CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCH2F, —OCHF2, —OCF₃, —OCH2CH₂F,—OCH3, —OCH2CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), —CH₂NH₂, and —CH₂CH₂NH₂. In yet a further aspect, eachof R^(21a), R^(21b), R^(21c), R^(21d) and, R^(21c) are independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, —CH₂F,—CHF₂, —CF₃, —CH₂C₁, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCH2F, —OCHF2,—OCF3, —OCH3, —NHCH3, —N(CH₃)₂, and —CH₂NH₂.

In a further aspect, each of R^(21a), R^(21b), R^(21c), R^(21d), andR^(21c) are independently selected from hydrogen, halogen, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ alkoxy. In a still furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and r^(21c) areindependently selected from hydrogen, —F, —Cl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂C₁, —CHCl₂, —CCl₃, —CH₂CH₂C₁,—CH₂CH₂CH₂C₁, —CH(CH₃)CH₂C₁, —OCH₂F, —OCHF2, —OCF₃, —OCH2CH₂F,—OCH2CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH3, —OCH2CH₃, —OCH2CH₂CH₃, and—OCH(CH₃)₂. In yet a further aspect, each of R^(21a), R^(21b), R^(21c),R^(21d), and R^(21c) are independently selected from hydrogen, —F, —Cl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂C₁, —CHCl₂, —CCl₃, —CH₂CH₂C₁, —OCH₂F,—OCHF2, —OCF₃, —OCH2CH₂F, —OCH3, and —OCH2CH₃. In an even furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen, —F, —Cl, —CH₂F, —CHF₂, —CF₃,—CH₂C₁, —CHCl₂, —CCl₃, —OCH₂F, —OCHF₂, —OCF₃, and —OCH₃.

In a further aspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R²are independently selected from hydrogen and halogen. In a still furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen, —F, —Cl, and —Br. In yet a furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen, —F, and —C₁. In an even furtheraspect, each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen and —C₁. In a still further aspect,each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen and —F.

In a further aspect, each of R^(21a), R^(21b), R^(21c), R^(21d), andR^(21e) is hydrogen.

h. Ar¹ Groups

In one aspect, Ar¹ is selected from aryl and heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a further aspect, Ar¹ is selected from aryl andheteroaryl, and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a still further aspect, Ar¹ is selected from aryl andheteroaryl, and is substituted with 0 or 1 group selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet afurther aspect, Ar¹ is selected from aryl and heteroaryl, and ismonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl,C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In an even furtheraspect, Ar¹ is selected from aryl and heteroaryl, and is unsubstituted.

In various aspects, Ar¹ is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. Examples of aryls include, but arenot limited to, phenyl, naphthyl, phenanthryl, and anthracenyl. Thus, ina further aspect, Ar¹ is aryl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, Ar¹ isaryl substituted with 0 or 1 group selected from halogen, —CN, —NH₂,—OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet afurther aspect, Ar¹ is aryl monosubstituted with a group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In an even further aspect, Ar¹ is unsubstituted aryl.

In various aspects, Ar¹ is C₆ aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect, Ar¹ is C₆ arylsubstituted with 0, 1, or 2 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In astill further aspect, Ar¹ is C₆ aryl substituted with 0 or 1 groupselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In yet a further aspect, Ar¹ is C₆ aryl monosubstituted witha group selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino,and C₁-C₄ aminoalkyl. In an even further aspect, Ar¹ is unsubstituted C₆aryl.

In various aspects, Ar¹ is heteroaryl substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. Examples ofheteroaryls include, but are not limited to, pyrrole, furan, thiophene,pyridine, pyridazine, pyrimidine, pyrazine, triazine, purine, oxazole,benzo[d]oxazole, benzo[d]thiazole, indole, and isoxazole. Thus, in afurther aspect, Ar¹ is heteroaryl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, Ar¹ isheteroaryl substituted with 0 or 1 group selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet afurther aspect, Ar¹ is heteroaryl monosubstituted with a group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In an even further aspect, Ar¹ is unsubstituted heteroaryl.

In various aspects, Ar¹ is selected from indolyl, pyridinyl,benzo[d]oxazole, and benzo[d]thiazole, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect,Ar¹ is selected from indolyl, pyridinyl, benzo[d]oxazole, andbenzo[d]thiazole, and is substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, Ar¹ isselected from indolyl, pyridinyl, benzo[d]oxazole, and benzo[d]thiazole,and is substituted with 0 or 1 group selected from halogen, —CN, —NH₂,—OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet afurther aspect, Ar¹ is selected from indolyl, pyridinyl,benzo[d]oxazole, and benzo[d]thiazole, and is monosubstituted with agroup selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino,and C₁-C₄ aminoalkyl. In an even further aspect, Ar¹ is Ar¹ is selectedfrom indolyl, pyridinyl, benzo[d]oxazole, and benzo[d]thiazole, and isunsubstituted.

In various aspects, Ar¹ is indolyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect, Ar¹ is indolylsubstituted with 0, 1, or 2 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In astill further aspect, Ar¹ is indolyl substituted with 0 or 1 groupselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In yet a further aspect, Ar¹ is indolyl monosubstituted witha group selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino,and C₁-C₄ aminoalkyl. In an even further aspect, Ar¹ is unsubstitutedindolyl.

In various aspects, Ar¹ is benzo[d]oxazolyl substituted with 0, 1, 2, or3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect,Ar¹ is benzo[d]oxazolyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a still further aspect, Ar¹ is benzo[d]oxazolylsubstituted with 0 or 1 group selected from halogen, —CN, —NH₂, —OH,—NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl,C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet a furtheraspect, Ar¹ is benzo[d]oxazolyl monosubstituted with a group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In an even further aspect, Ar¹ is unsubstitutedbenzo[d]oxazolyl.

In various aspects, Ar¹ is benzo[d]thiazolyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect,Ar¹ is benzo[d]thiazolyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl,C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄)dialkylamino, and C₁-C₄ aminoalkyl. In a still further aspect, Ar¹ isbenzo[d]thiazolyl substituted with 0 or 1 group selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In yet afurther aspect, Ar¹ is benzo[d]thiazolyl monosubstituted with a groupselected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy,C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In an even further aspect, Ar¹ is unsubstitutedbenzo[d]thiazolyl.

i. Ar² Groups

In one aspect, Ar² is C₆ aryl para-substituted with a—(CH₂)_(m)NR^(20a)NR^(20b) group, and substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In a further aspect,Ar² is C₆ aryl para-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group,and substituted with 0, 1, or 2 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄aminoalkyl. In a still further aspect, Ar² is C₆ aryl para-substitutedwith a —(CH₂)_(m)NR^(20a)R^(20b) group, and substituted with 0 or 1group selected from halogen, —CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino,and C₁-C₄ aminoalkyl. In yet a further aspect, Ar² is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, andmonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl,C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl. In an even furtheraspect, Ar² is C₆ aryl para-substituted with a —(CH₂)_(m)NR^(20a)R^(20b)group, and substituted with 0 other groups. 2. EXAMPLE DIPEPTIDE ANALOGS

In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

It is contemplated that one or more compounds can optionally be omittedfrom the disclosed invention.

It is understood that the disclosed compounds can be used in connectionwith the disclosed methods, compositions, kits, and uses.

It is understood that pharmaceutical acceptable derivatives of thedisclosed compounds can be used also in connection with the disclosedmethods, compositions, kits, and uses. The pharmaceutical acceptablederivatives of the compounds can include any suitable derivative, suchas pharmaceutically acceptable salts as discussed below, isomers,radiolabeled analogs, tautomers, and the like.

C. Pharmaceutical Compositions

In one aspect, disclosed are pharmaceutical compositions comprising adisclosed compound, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

Thus, in one aspect, disclosed are pharmaceutical compositionscomprising a therapeutically effective amount of a compound having astructure represented by a formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and -R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Ar^(e) is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

In various aspects, the compounds and compositions of the invention canbe administered in pharmaceutical compositions, which are formulatedaccording to the intended method of administration. The compounds andcompositions described herein can be formulated in a conventional mannerusing one or more physiologically acceptable carriers or excipients. Forexample, a pharmaceutical composition can be formulated for local orsystemic administration, intravenous, topical, or oral administration.

The nature of the pharmaceutical compositions for administration isdependent on the mode of administration and can readily be determined byone of ordinary skill in the art. In various aspects, the pharmaceuticalcomposition is sterile or sterilizable. The therapeutic compositionsfeatured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used includebuffers (for example, citrate buffer, phosphate buffer, acetate buffer,and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, polypeptides (for example, serum albumin), EDTA, sodiumchloride, liposomes, mannitol, sorbitol, water, and glycerol. Thenucleic acids, polypeptides, small molecules, and other modulatorycompounds featured in the invention can be administered by any standardroute of administration. For example, administration can be parenteral,intravenous, subcutaneous, or oral. A modulatory compound can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made foradministration by drops into the ear, for injection, or for ingestion;gels or powders can be made for ingestion or topical application.Methods for making such formulations are well known and can be found in,for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro,ed., Mack Publishing Co., Easton, Pa. 1990.

In various aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In various aspects, the pharmaceutical compositions of this inventioncan include a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of the compounds of the invention. Thecompounds of the invention, or pharmaceutically acceptable saltsthereof, can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an evenfurther aspect, the human is a patient.

In a further aspect, the pharmaceutical composition is used to treat adisorder of uncontrolled cellular proliferation such as, for example,cancers including, but not limited to, sarcomas, carcinomas,hematological cancers, solid tumors, breast cancer, cervical cancer,gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer,prostate cancer, ovarian cancer, bladder cancer, thyroid cancer,testicular cancer, pancreatic cancer, endometrial cancer, melanomas,gliomas, leukemias, lymphomas, chronic myeloproliferative disorders,myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cellneoplasms (myelomas).

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

D. Methods of Making Dipeptides

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Routes I-III, as described andexemplified below. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

1. Route I

In one aspect, substituted dipeptides can be prepared as shown below.

Compounds are represented in generic form, wherein PG is an amineprotecting group and with other substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forthbelow.

In one aspect, compounds of type 1.8, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.7 can be prepared by a coupling reaction between an appropriate amine,e.g., 1.5 as shown above, and an appropriate carboxylic acid, e.g., 1.6as shown above. Appropriate amines and appropriate carboxylic acids arecommercially available or prepared by methods known to one skilled inthe art. The coupling reaction is carried out in the presence of anappropriate coupling agent, e.g.,1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) as shown above, and an appropaitebase, e.g., N,N-diisopropylethylamine (DIPEA) as shown above, in anappropriate solvent, e.g., acetonitrile (CH₃CN) as shown above.Compounds of type 1.8 can be prepared by deprotection of an appropriateprotected amine, e.g., 1.7 as shown above. The deprotection is carriedout in the presence of an appropriate acid, e.g., trifluoroacetic acid(TFA) as shown above, in an appropriate solvent, e.g., dichloromethane(DCM) as shown above. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.1, 1.2, and 1.3), can besubstituted in the reaction to provide dipeptide analogs similar toFormula 1.4.

2. Route II

In one aspect, substituted dipeptides can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 2.4, and similar compounds, can beprepared according to reaction Scheme 2B above. Thus, compounds of type2.4 can be prepared by a coupling reaction between an appropriate amine,e.g., 1.8 as shown above, and an appropriate carboxylic acid, e.g., 2.3as shown above. Appropriate amines and appropriate carboxylic acids arecommercially available or prepared by methods known to one skilled inthe art. The coupling reaction is carried out in the presence of anappropriate coupling agent, e.g., HATU as shown above, and an appropaitebase, e.g., DIPEA as shown above, in an appropriate solvent, e.g.,dimethylformamide (DMF) as shown above. As can be appreciated by oneskilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 1.4,and 2.1), can be substituted in the reaction to provide dipeptideanalogs similar to Formula 2.2.

3. Route III

In one aspect, substituted dipeptides can be prepared as shown below.

Compounds are represented in generic form, wherein PG is an amineprotecting group and with other substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forthbelow.

In one aspect, compounds of type 3.3, and similar compounds, can beprepared according to reaction Scheme 3B above. Thus, compounds of type3.3 can be prepared by deprotection of an appropriate protected amine,e.g., 2.4 as shown above. Appropriate protected amines are commerciallyavailable or prepared by methods known to one skilled in the art. Thedeprotection is carried out in the presence of an appropriate base,e.g., piperidine as shown above, in an appropriate solvent, e.g., DMF asshown above. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 3.1), can be substituted in the reaction to providedipeptide analogs similar to Formula 3.2.

E. Treating a Disorder of Uncontrolled Cellular Proliferation

In one aspect, disclosed are methods of treating a disorder ofuncontrolled cellular proliferation in a subject, the method comprisingthe step of administering to the subject an effective amount of at leastone disclosed compound, or a pharmaceutically acceptable salt thereof.

Thus, in one aspect, disclosed are methods for treating a disorder ofuncontrolled cellular proliferation in a subject, the method comprisingadministering to the subject an effective amount of a compound having astructure represented by a formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b)b, —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Are is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof, thereby treating the disorder.

In a further aspect, the subject has been diagnosed with a need fortreatment of the disorder prior to the administering step.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is a human.

In a further aspect, the method further comprises the step ofidentifying a subject in need of treatment of the disorder.

In a further aspect, the disorder is a cancer. In a still furtheraspect, the cancer is selected from a sarcoma, a carcinoma, ahematological cancer, a solid tumor, breast cancer, cervical cancer,gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer,prostate cancer, ovarian cancer, thyroid cancer, testicular cancer,pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma,leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplasticsyndrome, myeloproliferative neoplasm, non-small cell lung carcinoma,and plasma cell neoplasm (myeloma).

In a further aspect, the cancer is a solid tumor.

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the method further comprises the step ofadministering a therapeutically effective amount of at least one agentassociated with the treatment of a disorder of uncontrolled cellularproliferation. In a still further aspect, the at least one agent is achemotherapeutic agent. In yet a further aspect, the chemotherapeuticagent is selected from an alkylating agent, an antimetabolite agent, anantineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTorinhibitor agent.

In various aspects, the antineoplastic antibiotic agent is selected fromdoxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin,epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, andvalrubicin, or a pharmaceutically acceptable salt thereof.

In various aspects, the antimetabolite agent is selected fromgemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine,pemetrexed, fludarabine, nelarabine, cladribine, clofarabine,cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, andthioguanine, or a pharmaceutically acceptable salt thereof.

In various aspects, the alkylating agent is selected from carboplatin,cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine,busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide,mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin,or a pharmaceutically acceptable salt thereof.

In various aspects, the mitotic inhibitor agent is selected fromirinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel,etopside, vincristine, ixabepilone, vinorelbine, vinblastine, andteniposide, or a pharmaceutically acceptable salt thereof.

In various aspects, the mTor inhibitor agent is selected fromeverolimus, siroliumus, and temsirolimus, or a pharmaceuticallyacceptable salt, hydrate, solvate, or polymorph thereof.

In a further aspect, the at least one compound and the at least oneagent are administered sequentially. In a still further aspect, the atleast one compound and the at least one agent are administeredsimultaneously.

In a further aspect, the at least one compound and the at least oneagent are co-formulated. In a still further aspect, the at least onecompound and the at least one agent are co-packaged.

F. Modifying Programmed Death-Ligand-1 and/or Programmed Death-Ligand-2Signaling in a Subject

In one aspect, disclosed are methods of modifying PDL-1 and/or PDL-2signaling in a subject, the method comprising the step of administeringto the subject an effective amount of at least one disclosed compound,or a pharmaceutically acceptable salt thereof.

Thus, in one aspect, disclosed are methods for modifying PDL-1 and/orPDL-2 signaling in a subject, the method comprising administering to thesubject an effective amount of a compound having a structure representedby a formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Ar² is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof, thereby modifying PDL-1 and/or PDL-2 signalingin the subject.

In a further aspect, the disclosed methods modify PDL-1 signaling. In astill further aspect, the disclosed methods modify PDL-2 signaling. Inyet a further aspect, the disclosed methods modify both PDL-1 and PDL-2signaling.

In a further aspect, modifying is decreasing. In a still further aspect,modifying is inhibiting.

In a further aspect, the subject has been diagnosed with a disorder ofuncontrolled cellular proliferation prior to the administering step.

In a further aspect, the subject has been diagnosed with a need formodifying PDL-1 and/or PDL-2 signaling prior to the administering step.

In a further aspect, the subject has been diagnosed with a need fortreatment of a disorder associated with PDL-1 and/or PDL-2 signalingdysfunction prior to the administering step.

In a further aspect, the method further comprises the step ofidentifying a subject in need of treatment of a disorder associated withPDL-1 and/or PDL-2 signaling dysfunction.

G. Modifying Programmed Death-Ligand-1 and/or Programmed Death-Ligand-2in at Least One Cell

In one aspect, disclosed are methods of modifying PDL-1 and/or PDL-2signaling in a cell, the method comprising the step of contacting thecell with an effective amount of at least one disclosed compound, or apharmaceutically acceptable salt thereof.

Thus, in one aspect, disclosed are methods for modifying PDL-1 and/orPDL-2 signaling in a cell, the method comprising contacting the cellwith an effective amount of a compound having a structure represented bya formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Are is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof, thereby modifying PDL-1 and/or PDL-2 signalingin the cell.

In a further aspect, the disclosed methods modify PDL-1 signaling. In astill further aspect, the disclosed methods modify PDL-2 signaling. Inyet a further aspect, the disclosed methods modify both PDL-1 and PDL-2signaling.

In a further aspect, modifying is decreasing. In a still further aspect,modifying is inhibiting.

In a further aspect, the cell is mammalian. In a still further aspect,the cell is human.

In a further aspect, the cell has been isolated from a human prior tothe administering step.

In a further aspect, contacting is via administration to a subject. In astill further aspect, the subject has been diagnosed with a need formodification of PDL-1 and/or PDL-2 signaling prior to the administeringstep. In yet a further aspect, the subject has been diagnosed with aneed for treatment of a disorder associated with PDL-1 and/or PDL-2signaling dysfunction.

H. Additional Methods of Using the Compounds

The compounds and pharmaceutical compositions of the invention areuseful in treating or controlling disorders associated with uncontrolledcellular proliferation and in particular, cancer.

Examples of disorders of uncontrolled cellular proliferation for whichthe compounds and compositions can be useful in treating, include, butare not limited to, cancers such as, for example, sarcomas, carcinomas,hematological cancers, solid tumors, breast cancer, cervical cancer,gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer,prostate cancer, ovarian cancer, bladder cancer, thyroid cancer,testicular cancer, pancreatic cancer, endometrial cancer, melanomas,gliomas, leukemias, lymphomas, chronic myeloproliferative disorders,myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cellneoplasms (myelomas).

To treat or control the disorder, the compounds and pharmaceuticalcompositions comprising the compounds are administered to a subject inneed thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, areptile, or an amphibian. The subject can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. The subject is preferably a mammal, such as ahuman. Prior to administering the compounds or compositions, the subjectcan be diagnosed with a need for treatment of a disorder of uncontrolledcellular proliferation, such as cancer.

The compounds or compositions can be administered to the subjectaccording to any method. Such methods are well known to those skilled inthe art and include, but are not limited to, oral administration,transdermal administration, administration by inhalation, nasaladministration, topical administration, intravaginal administration,ophthalmic administration, intraaural administration, intracerebraladministration, rectal administration, sublingual administration, buccaladministration and parenteral administration, including injectable suchas intravenous administration, intra-arterial administration,intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent. A preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. A preparation can also be administeredprophylactically; that is, administered for prevention of a disorder ofuncontrolled cellular proliferation, such as cancer.

The therapeutically effective amount or dosage of the compound can varywithin wide limits. Such a dosage is adjusted to the individualrequirements in each particular case including the specific compound(s)being administered, the route of administration, the condition beingtreated, as well as the patient being treated. In general, in the caseof oral or parenteral administration to adult humans weighingapproximately 70 Kg or more, a daily dosage of about 10 mg to about10,000 mg, preferably from about 200 mg to about 1,000 mg, should beappropriate, although the upper limit may be exceeded. The daily dosagecan be administered as a single dose or in divided doses, or forparenteral administration, as a continuous infusion. Single dosecompositions can contain such amounts or submultiples thereof of thecompound or composition to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days.

1. Use of Compounds

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method. In a further aspect, a use relatesto the manufacture of a medicament for the treatment of a disorder ofuncontrolled cellular proliferation in a subject.

Also provided are the uses of the disclosed compounds and products. Inone aspect, the invention relates to use of at least one disclosedcompound; or a pharmaceutically acceptable salt, hydrate, solvate, orpolymorph thereof. In a further aspect, the compound used is a productof a disclosed method of making.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof, foruse as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof,wherein a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of the compound or the product of adisclosed method of making.

In various aspects, the use relates to a treatment of a disorder ofuncontrolled cellular proliferation in a subject. In one aspect, the useis characterized in that the subject is a human. In one aspect, the useis characterized in that the disorder of uncontrolled cellularproliferation is a cancer.

In a further aspect, the use relates to the manufacture of a medicamentfor the treatment of a disorder of uncontrolled cellular proliferationin a subject.

It is understood that the disclosed uses can be employed in connectionwith the disclosed compounds, products of disclosed methods of making,methods, compositions, and kits. In a further aspect, the inventionrelates to the use of a disclosed compound or a disclosed product in themanufacture of a medicament for the treatment of a disorder ofuncontrolled cellular proliferation in a mammal. In a further aspect,the disorder of uncontrolled cellular proliferation is a cancer.

2. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treating a disorder of uncontrolled cellularproliferation in a subject having the disorder, the method comprisingcombining a therapeutically effective amount of a disclosed compound orproduct of a disclosed method with a pharmaceutically acceptable carrieror diluent.

As regards these applications, the present method includes theadministration to an animal, particularly a mammal, and moreparticularly a human, of a therapeutically effective amount of thecompound effective in the treatment of a disorder of uncontrolledcellular proliferation. The dose administered to an animal, particularlya human, in the context of the present invention should be sufficient toaffect a therapeutic response in the animal over a reasonable timeframe. One skilled in the art will recognize that dosage will dependupon a variety of factors including the condition of the animal and thebody weight of the animal.

The total amount of the compound of the present disclosure administeredin a typical treatment is preferably between about 0.05 mg/kg and about100 mg/kg of body weight for mice, and more preferably between 0.05mg/kg and about 50 mg/kg of body weight for mice, and between about 100mg/kg and about 500 mg/kg of body weight, and more preferably between200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.This total amount is typically, but not necessarily, administered as aseries of smaller doses over a period of about one time per day to aboutthree times per day for about 24 months, and preferably over a period oftwice per day for about 12 months.

The size of the dose also will be determined by the route, timing andfrequency of administration as well as the existence, nature and extentof any adverse side effects that might accompany the administration ofthe compound and the desired physiological effect. It will beappreciated by one of skill in the art that various conditions ordisease states, in particular chronic conditions or disease states, mayrequire prolonged treatment involving multiple administrations.

Thus, in one aspect, the invention relates to the manufacture of amedicament comprising combining a disclosed compound or a product of adisclosed method of making, or a pharmaceutically acceptable salt,solvate, or polymorph thereof, with a pharmaceutically acceptablecarrier or diluent.

3. Kits

In one aspect, disclosed are kits comprising an effective amount of adisclosed compound, and one or more of: (a) at least one agentassociated with the treatment of a disorder of uncontrolled cellularproliferation; (b) instructions for administering the compound inconnection with treating a disorder of uncontrolled cellularproliferation; and (c) instructions for treating a disorder ofuncontrolled cellular proliferation.

Thus, in one aspect, disclosed are kits comprising an effective amountof a compound having a structure represented by a formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁- C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Are is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, providedthat when each of R^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈alkyl, and provided that when n is 0, then each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl or each of R^(5a) and R^(5b) are covalentlybonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group, and R⁶ is hydrogen, or a pharmaceuticallyacceptable salt thereof, and one or more of: (a) at least one agentassociated with the treatment of a disorder of uncontrolled cellularproliferation; (b) instructions for administering the compound inconnection with treating a disorder of uncontrolled cellularproliferation; and (c) instructions for treating a disorder ofuncontrolled cellular proliferation.

In a further aspect, the disorder is a cancer. In a still furtheraspect, the cancer is selected from a sarcoma, a carcinoma, ahematological cancer, a solid tumor, breast cancer, cervical cancer,gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer,prostate cancer, ovarian cancer, thyroid cancer, testicular cancer,pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma,leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplasticsyndrome, myeloproliferative neoplasm, non-small cell lung carcinoma,and plasma cell neoplasm (myeloma).

In a further aspect, the cancer is a solid tumor.

In a further aspect, the agent is a chemotherapeutic agent. In yet afurther aspect, the chemotherapeutic agent is selected from analkylating agent, an antimetabolite agent, an antineoplastic antibioticagent, a mitotic inhibitor agent, and a mTor inhibitor agent.

In various aspects, the antineoplastic antibiotic agent is selected fromdoxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin,epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, andvairubicin, or a pharmaceutically acceptable salt thereof.

In various aspects, the antimetabolite agent is selected fromgemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine,pemetrexed, fludarabine, nelarabine, cladribine, clofarabine,cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, andthioguanine, or a pharmaceutically acceptable salt thereof.

In various aspects, the alkylating agent is selected from carboplatin,cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine,busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide,mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin,or a pharmaceutically acceptable salt thereof.

In various aspects, the mitotic inhibitor agent is selected fromirinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel,etopside, vincristine, ixabepilone, vinorelbine, vinblastine, andteniposide, or a pharmaceutically acceptable salt thereof.

In various aspects, the mTor inhibitor agent is selected fromeverolimus, siroliumus, and temsirolimus, or a pharmaceuticallyacceptable salt, hydrate, solvate, or polymorph thereof.

In a further aspect, the compound and the agent are co-formulated. In afurther aspect, the compound and the agent are co-packaged.

In a further aspect, the compound and the agent are administeredsequentially. In a still further aspect, the compound and the agent areadministered simultaneously.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is understood that the disclosed kits can be prepared from thedisclosed compounds, products, and pharmaceutical compositions. It isalso understood that the disclosed kits can be employed in connectionwith the disclosed methods of using.

The foregoing description illustrates and describes the disclosure.

Additionally, the disclosure shows and describes only the preferredembodiments but, as mentioned above, it is to be understood that it iscapable to use in various other combinations, modifications, andenvironments and is capable of changes or modifications within the scopeof the invention concepts as expressed herein, commensurate with theabove teachings and/or the skill or knowledge of the relevant art. Theembodiments described herein above are further intended to explain bestmodes known by applicant and to enable others skilled in the art toutilize the disclosure in such, or other, embodiments and with thevarious modifications required by the particular applications or usesthereof. Accordingly, the description is not intended to limit theinvention to the form disclosed herein. Also, it is intended to theappended claims be construed to include alternative embodiments.

All publications and patent applications cited in this specification areherein incorporated by reference, and for any and all purposes, as ifeach individual publication or patent application were specifically andindividually indicated to be incorporated by reference. In the event ofan inconsistency between the present disclosure and any publications orpatent application incorporated herein by reference, the presentdisclosure controls.

I. EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Chemistry Experimentals

All reactions were carried out in an oven- or flame-dried glasswareunder argon atmosphere using standard gas-tight syringe, cannula, andsepta. The reaction temperatures were measured externally. Stirring wasachieved with oven dried magnetic bars. All the reactions were done inanhydrous solvents (DMF, MeCN, CH₂C₁₂) purchased from Sigma-Aldrich. Allcommercially purchased reagents were used without purification. Thereactions were monitored by thin-layer chromatography (TLC) on apre-coated silica gel (60F254) glass/aluminum plates from EMD Milliporeand visualized using UV light (254 nm).

Purification of the compounds was performed on Teledyne-ISCO CombiflashRf 200 purification system by using Redisep Rf® normal phase silica gelcolumns 230-400 mesh. Proton NMR spectra were recorded on a Varian Unity400 NMR spectrometer operating at 400 MHz calibrated to the solvent peakand TMS peak. The chemical formula and Exact Mass for target compoundswere determined from the (M+H)⁺ by high resolution mass spectroscopyusing an Agilent 6210 Electrospray Time of Flight. ESI-MS spectra wererecorded on a BioTof-2 time-of-flight mass spectrometer.

a. Synthesis of Compound No. 1

(9H-fluoren-9-yl)methyl tert-butyl(5-((1-amino-2-methyl-1oxopropan-2-yl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamate(iii). To a solution of 2-amino-2-methylpropanamide, i (0.700 g, 3.24mmol) and(R)-5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoicacid, ii (1.47 g, 3.24 mmol) in Acetonitrile (14 mL), was added HATU(1.85 g, 4.86 mmol) under nitrogen. After 5 mins,N,N-Diisopropylethylamine (1.70 mL, 9.72 mmol) was added to the reactionmixture and allowed to stir at room temperature. After overnightstirring TLC indicated completion of reaction. The reaction mixture wasconcentrated under vacuum and taken up in EtOAc (200 mL). Organic layerwas washed with saturated solution of NaHCO₃ (3×50 mL), water (1×50 mL),brine (1×50 mL) and dried over anhydrous Na₂SO₄. The drying agent wasfiltered and filtrate was concentrated under vacuum to obtain the crudeproduct. The crude product was purified on Teledyne ISCO Combiflash® Rfpurification machine using MeOH/DCM to afford (9H-fluoren-9-yl)methyltert-butyl(5-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamate,iii (1.50 g, 86%) as a colorless solid. ESI-MS m/z: 539.2 (M+H); ¹H NMR(400 MHz, DMSO-d₆) δ 7.95-7.86 (m, 3H), 7.68 (d, J=7.4 Hz, 2H),7.44-7.38 (m, 2H), 7.33 (td, J=7.4, 1.2 Hz, 2H), 7.26 (t, J=5.6 Hz, 1H),6.97 (dd, J=24.9, 10.0 Hz, 3H), 4.33-4.17 (m, 3H), 3.84-3.74 (m, 1H),2.96 (q, J=6.4 Hz, 2H), 1.64-1.30 (m, 19H).

(9H-fluoren-9-yl)methyl(R)-(4-amino-5-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxopentyl)carbamate(iv). Trifluoroacetic acid (2.13 mL, 27.8 mmol) was added dropwsie to asolution of (9H-fluoren-9-yl)methyl tert-butyl(5-((1-amino-2-methyl-1oxopropan-2-yl)amino)-5-oxopentane-1,4-diyl)(R)-dicarbamate,iii (1.50 g, 2.78 mmol) in DCM (20 mL) under nitrogen. The resultingmixture was stirred overnight at room temperature and TLC indicatedcompletion of the reaction. Reaction mixture was concentrated undervacuum and the crude product was purified on Teledyne ISCO Combiflash®Rf purification machine using MeOH/DCM to afford(9H-fluoren-9-yl)methyl(R)-(4-amino-5-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxopentyl)carbamate,iv (1.10 g, 90%) as a colorless solid. ESI-MS m/z: 439.2 (M+H); ¹H NMR(400 MHz, DMSO-d₆) δ8.37 (s, 1H), 8.02-7.87 (m, 4H), 7.68 (d, J=7.5 Hz,2H), 7.42 (td, J=7.5, 1.1 Hz, 2H), 7.38-7.31 (m, 3H), 7.03 (d, J=31.2Hz, 2H), 4.30 (d, J=6.9 Hz, 2H), 4.21 (t, J=6.8 Hz, 1H), 3.76 (t, J=6.4Hz, 1H), 2.99 (q, J=6.6 Hz, 2H), 1.76-1.59 (m, 2H), 1.49-1.34 (m, 8H).

(9H-fluoren-9-yl)methyl(R)-(5-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxo-4-(2-phenylacetamido)pentyl)carbamate(vi). To a solution of(9H-fluoren-9-yl)methyl(R)-(4-amino-5-((l-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxopentyl)carbamate,iv (0.100 g, 0.228 mmol) and phenylacetic acid, v (0.031 g, 0.228 mmol)in DMF (1 mL), was added HATU (0.130 g, 0.342 mmol) under nitrogen.After 5 mins, N,N-Diisopropylethylamine (0.12 mL, 0.684 mmol) was addedto the reaction mixture and allowed to stir at room temperature. Afterovernight stirring TLC indicated completion of the reaction. Thereaction mixture was concentrated under vacuum and taken up in EtOAc (75mL). Organic layer was washed with a saturated solution of NaHCO₃ (3×30mL), water (1×30 mL), brine (1×30 mL) and dried over anhydrous Na₂SO₄.The drying agent was filtered and filtrate was concentrated under vacuumto obtain the crude product. The crude product was purified on TeledyneISCO Combiflash® Rf purification machine using MeOH/DCM to afford(9H-fluoren-9-yl)methyl(R)-(5-((l-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxo-4-(2-phenylacetamido)pentyl)carbamate,vi (0.085 g, 67%) as a colorless solid. ESI-MS m/z: 557.2 (M+H); ¹H NMR(400 MHz, DMSO-d₆) δ 8.27 (d, J=6.8 Hz, 1H), 7.94-7.86 (m, 3H),7.71-7.65 (m, 2H), 7.44-7.16 (m, 10H), 6.93 (s, 1H), 6.84 (s, 1H), 4.29(d, J 6.4 Hz, 2H), 4.21 (t, J=6.9 Hz, 1H), 4.10 (q, J=7.0 Hz, 1H), 3.47(q, J=14.0 Hz, 2H), 2.97 (q, J=6.5 Hz, 2H), 1.69-1.26 (m, 10H).

(R)-5-amino-N-(1-amino-2-methyl-1-oxopropan-2-yl)-2-(2-phenylacetamido)pentanamide(1). Piperidine (0.071 mL, 0.719 mmol) was added to a solution of(9H-fluoren-9-yl)methyl(R)-(5-((1-amino-2-methyl-1-oxopropan-2-yl)amino)-5-oxo-4-(2-phenylacetamido)pentyl)carbamate,vi (0.080 g, 0.144 mmol) in anhydrous DMF (0.7 mL) under nitrogen. Theresulting mixture was allowed to stir at room temperature. After ˜3h,mass spec indicated completion of the reaction. The reaction mixture wasconcentrated under vacuum and crude product was washed with diethyletherseveral times. The product was taken into water and dried on lyophylizerovernight to afford(R)-5-amino-N-(1-amino-2-methyl-1-oxopropan-2-yl)-2-(2-phenylacetamido)pentanamide,1 (0.042 g, 87%) as a white solid. ESI-MS m/z: 335.2 (M+H); ¹H NMR (400MHz, Methanol-d₄) δ 7.33-7.20 (m, 5H), 4.19 (dd, J=8.2, 6.0 Hz, 1H),3.57 (s, 2H), 2.75 (s, 2H), 1.86-1.51 (m, 4H), 1.45 (s, 3H), 1.43 (s,3H). HRMS calcd for [C₁₇H₂₆N₄O₃+H]+: 334.2005, Found: 334.2008.

All other analogs were synthesized by following the above syntheticprocedures.

2. Evaluation of Dipeptides

A list of compounds evaluated is shown in Table 1 below.

TABLE 1 EC50 Min/Max ¹H NMR (μM) % HRMS/ (400 MHz, DMSO-d6 No. StructureKD Luciferase Luciferase LCMS or MeOH-d₄) 1

4.29E− 08 17.98 30.25/ 53.84 Calculated: 334.2005, Found: 334.2008 δ7.33-7.20 (m, 5H), 4.19 (dd, J = 8.2, 6.0 Hz, 1H), 3.57 (s, 2H), 2.75(s, 2H), 1.86-1.51 (m, 4H), 1.45 (s, 3H), 1.43 (s, 3H) 2

3.00E− 08 7.9  28.9/ 49.53 Calculated: 334.2005, Found: 334.2002 δ 8.45(d, J = 6.9 Hz, 1H), 8.04 (s, 1H), 7.31-7.17 (m, 5H), 7.00 (s, 1H), 6.83(s, 1H), 4.13-4.03 (m, 1H), 3.61-3.33 (m, 2H), 2.57 (t, J = 6.8 Hz, 2H),1.73- 1.35 (m, 4H), 1.33 (s, 3H), 1.31 (s, 3H) 3

1.37E− 05 0.01 32.56/ 53.48 Calculated: 402.1879, Found: 402.1879 δ 8.63(s, 1H), 8.09 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 7.9 Hz,2H), 6.99 (s, 1H), 6.82 (s, 1H), 4.11 (q, J = 6.8, 6.3 Hz, 1H),3.66-3.56 (m, 2H), 2.62 (bs, 2H), 1.73-1.37 (m, 4H), 1.33 (s, 3H), 1.31(s, 3H) 4

9.06E− 08 0.47 36.23/ 62.05 Calculated: 352.1911, Found: 352.1905. δ8.51 (d, J = 7.1 Hz, 1H), 8.07 (s, 1H), 7.33-7.25 (m, 2H), 7.14-7.07 (m,2H), 7.00 (s, 1H), 6.82 (s, 1H), 4.11 (q, J = 7.0 Hz, 1H), 3.53-3.42 (m,2H), 2.64 (t, J = 7.0 Hz, 2H), 1.73- 1.36 (m, 4H), 1.34 (s, 3H), 1.31(s, 3H) 5

3.18E− 05 0.32  7.37/ 13.51 Calculated: 364.2111, Found: 364.212 δ 8.46(d, J = 6.9 Hz, 1H), 8.10 (s, 1H), 7.23-7.16 (m, 2H), 7.04 (s, 1H),6.86- 6.81 (m, 2H), 6.80 (s, 1H), 4.10 (q, J = 7.4 Hz, 1H), 3.71 (s,3H), 3.44-3.33 (m, 2H), 2.67 (t, J = 6.9 Hz, 2H), 1.75-1.39 (m, 4H),1.33 (s, 3H), 1.31 (s, 3H) 6

3.30E− 08 0.09   6.4/ 12.32 Calculated: 418.1828, Found: 418.1822 δ 8.59(d, J = 7.0 Hz, 1H), 8.07 (s, 1H), 7.42-7.35 (m, 2H), 7.30-7.22 (m, 2H),7.00 (s, 1H), 6.82 (s, 1H), 4.10 (q, J = 6.9 Hz, 1H), 3.59-3.48 (m, 2H),2.61 (t, J = 6.9 Hz, 2H), 1.72- 1.34 (m, 4H), 1.32 (s, 3H), 1.30 (s, 3H)7

1.70E− 05 0.28 23.3/ 31.84 Calculated: 360.2161, Found: 360.2166 δ 8.49(d, J = 6.5 Hz, 1H), 8.16 (s, 1H), 7.32-7.17 (m, 5H), 6.96 (s, 1H), 6.75(s, 1H), 4.08 (q, J = 6.7 Hz, 1H), 3.54-3.42 (m, 2H), 2.63 (t, J = 6.9Hz, 2H), 2.10-2.00 (m, 1H), 1.96- 1.80 (m, 3H), 1.72-1.34 (m, 8H) 8

2.81E− 06 1.37 27.29/ 35.26 Calculated: 348.2161, Found: 334.2168 δ 8.43(d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.30-7.17 (m, 5H), 7.01 (s, 1H), 6.82(s, 1H), 4.09 (q, J = 7.0 Hz, 1H), 3.53-3.42 (m, 2H), 2.64 (t, J = 7.4Hz, 2H), 1.67-1.19 (m, 12H) 9

3.67E− 06 0.05 19.82/ 30.48 Calculated: 352.1911, Found: 352.1911 δ 8.49(d, J = 7.1 Hz, 1H), 8.09 (s, 1H), 7.36-7.23 (m, 2H), 7.16-7.09 (m, 2H),6.99 (s, 1H), 6.82 (s, 1H), 4.16 (q, J = 7.0 Hz, 1H), 3.61-3.51 (m, 2H),2.70 (t, J = 6.9 Hz, 2H), 1.78-1.44 (m, 4H), 1.35 (s, 3H), 1.33 (s, 3H)10

3.61E− 08 Inactive Calculated: 348.2161, Found: 348.2168 δ 8.50 (d, J =7.1 Hz, 1H), 8.16 (s, 1H), 7.20-7.06 (m, 4H), 7.02 (s, 1H), 6.80 (s,1H), 4.12 (q, J = 7.2 Hz, 1H), 3.49-3.37 (m, 2H), 2.89 (t, J = 7.2 Hz,3H), 2.25 (s, 3H), 1.79-1.47 (m, 4H), 1.33 (s, 3H), 1.31 (s, 3H) 11

2.35E− 06 1.28 19.25/ 27.39 Calculated: 352.1911, Found: 352.1917 δ 8.60(s, 1H), 8.11 (s, 1H), 7.37-7.26 (m, 1H), 7.14-6.96 (m, 4H), 6.81 (s,1H), 4.13 (q, J = 7.2 Hz, 1H), 3.53 (s, 2H), 2.69 (t, J = 6.8 Hz, 2H),1.77-1.46 (m, 4H), 1.34 (s, 3H), 1.34 (s, 3H) 12

3.70E− 06 Inactive Calculated: 362.2318, Found: 362.232 δ 8.42 (bs, 1H),7.94 (s, 1H), 7.47-7.18 (m, 5H), 7.05 (s, 1H), 6.85 (s, 1H), 4.17 (q, J= 7.5 Hz, 1H), 2.67 (t, J = 6.7 Hz, 2H), 1.78-1.36 (m, 10H), 1.32 (s,3H), 1.30 (s, 3H) 13

1.83E− 06 1.28 25.09/ 30.85 Calculated: 373.2114, Found: 373.2107 δ8.29-8.04 (m, 4H), 7.47 (d, J = 8.1 Hz, 1H), 7.25-7.08 m, 3H), 6.82 (s,1H), 4.34 (q, J = 7.1 Hz, 1H), 3.81 (s, 3H), 2.74 (bs, 2H), 1.83-1.45(m, 4H), 1.37 (s, 3H), 1.34 (s, 3H) 14

4.38E− 06 0.11 20.36/ 27.8  m/z = 333 [M + H]⁺ δ 7.32-7.31 (m, 4H),7.28- 7.23 (m, 1H), 4.05 (t, J = 7.2 Hz, 1H), 3.59 (s, 2H), 2.73 (t, J =7.2 Hz, 2H), 1.83-1.64 (m, 2H), 1.60- 1.37 (m, 4H), 1.05-0.95 (m, 2H) 15

6.70E− 08 3.32 20.14/ 30.07 m/z = 351 [M + H]⁺ δ 7.33-7.30 (m, 2H), 7.05(t, J = 6.4 Hz, 2H), 4.03 (t, J = 6.8 Hz, 1H), 3.58 (s, 2H), 2.68 (t, J= 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.55-1.45 (m, 3H), 1.41-1.38 (m, 1H),1.02-1.00 (m, 2H) 16

1.70E− 05 6.19 27.49/ 48.16 Calculated: 373.1816, Found: 373.181 δ 8.00(s, 1H), 7.61-7.45 (m, 5H), 6.83 (s, 2H), 4.16 (q, J = 5.4 Hz, 1H),2.42.44 (m, 2H), 1.77-1.61 (m, 2H), 1.35-1.24 (m, 8H) 17

No Binding 10.31 18.02/ 29.55 Calculated: 368.1617, Found: 368.1607 δ8.51 (d, J = 6.9 Hz, 1H), 7.95 (s, 1H), 7.35-7.29 (m, 2H), 7.27-7.22 (m,2H), 6.90 (s, 1H), 6.82 (s, 1H), 4.06 (q, J = 6.9 Hz, 1H), 3.52- 3.38(m, 2H), 2.55-2.49 (m, 2H), 1.78-1.43 (m, 4H), 1.32 (s, 3H), 1.29 (s,3H) 18

8.60E− 06 20.38 28.65/ 62.58 Calculated: 388.1722, Found: 388.1724 δ7.74-7.62 (m, 2H), 7.28- 7.16 (m, 2H), 4.28 (dd, J = 8.4, 6.1 Hz, 1H),2.74 (s, 2H), 1.91-1.51 (m, 4H), 1.46 (s, 3H), 1.44 (s, 3H) 19

5.70E− 06 18.31 25.66/ 52.24 Calculated: 324.1598, Found: 324.1600 δ7.35-7.25 (m, 2H), 7.08- 6.97 (m, 2H), 4.27 (dd, J = 8.2, 5.9 Hz, 1H),3.88-3.84 (m, 2H), 3.57 (s, 2H), 2.78 (t, J = 7.3 Hz, 2H), 1.88- 1.57(m, 4H) 20

No Binding 0.49 37.06/ 62.99 Calculated: 306.1692, Found: 306.1695 δ7.37-7.13 (m, 5H), 4.27 (dd, J = 8.2, 5.9 Hz, 1H), 3.86-3.78 (m, 2H),3.58 (d, J = 1.7 Hz, 2H), 2.73 (t, J = 7.2 Hz, 2H), 1.89-1.52 (m, 4H) 21

1.12E− 05 4.3 42.66/ 59.57 Calculated: 338.1754, Found: 338.1759 δ7.95-7.87 (m, 2H), 7.22- 7.12 (m, 2H), 4.40 (dd, J = 8.5, 6.1 Hz, 1H),2.78 (t, J = 7.2 Hz, 2H), 1.97-1.55 (m, 4H), 1.51 (s, 3H), 1.48 (s, 3H)22

9.44E− 04 2.05 11.67/ 18.73 Calculated: 360.2161, Found: 360.2164 δ7.52-7.22 (m, 5H), 4.26 (dd, J = 7.4, 5.7 Hz, 1H), 2.69 (t, J = 7.1 Hz,2H), 1.78-1.65 (m, 1H), 1.58- 1.38 (m, 11H), 1.19-1.02 (m, 2H) 23

No Binding 17.7 28.06/ 46.24 m/z = 397 [M + H]⁺ δ 7.33-7.27 (m, 1H),7.30- 7.23 (m, 3H), 7.27-7.18 (m, 5H), 4.49-4.46 (m, 1H), 3.81 (s, 2H),3.52 (s, 2H), 3.09-3.04 (m, 1H), 2.96-2.91 (m, 1H), 1.34 (s, 3H), 1.31(s, 3H) 24

3.36E− 04 0.714 18.77/ 29.82 m/z = 415 [M + H]⁺ δ 7.28 (d, J = 8.2 Hz,2H), 7.25-7.17 (m, 4H), 7.06-6.95 (m, 2H), 4.50-4.46 (m, 1H), 3.83 (s,2H), 3.50 (s, 2H), 3.09-3.05 (m, 1H), 2.95-2.91 (m, 1H), 1.39 (s, 3H),1.35 (s, 3H) 25

5.26E− 07 5.03 24.29/ 38.96 Calculated: 378.2067, Found: 378.2067 δ7.48-7.41 (m, 2H), 7.16- 7.07 (m, 2H), 4.28 (dd, J = 7.1, 5.7 Hz, 1H),2.78 (t, J = 7.0 Hz, 2H), 1.81-1.69 (m, 1H), 1.63-1.41 (m, 11H),1.15-1.04 (m, 2H) 26

1.19E− 04 3.79 17.75/ 29.54 Calculated: 380.2224, Found: 380.2223 δ7.41-7.34 (m, 2H), 7.10- 7.01 (m, 2H), 4.27 (dd, J = 1.6, 6.0 Hz, 1H),2.87 (t, J = 13 Hz, 2H), 1.87-1.41 (m, 16H) 27

2.40E− 05 10.25 30.68/ 38.5 Calculated: 386.1521, Found: 386.1521 δ 7.37(dd, J = 8.6, 6.0 Hz, 1H), 7.22 (dd, J = 8.7, 2.7 Hz, 1H), 7.05 (td, J =8.4, 2.7 Hz, 1H), 4.23 (dd, J = 8.0, 6.0 Hz, 1H), 3.80-3.66 (m, 2H),2.78 (t, J = 7.2 Hz, 2H), 1.92-1.52 (m, 4H), 1.48 (s, 3H), 1.46 (s, 3H)28

7.64E− 05 2.0 20.56/ 34.27 Calculated: 370.1816, Found: 370.1817 δ7.25-7.13 (m, 2H), 7.11- 7.03 (m, 1H), 4.21 (dd, J = 7.7, 6.2 Hz, 1H),3.61-3.49 (m, 2H), 2.82 (t, J = 7.2 Hz, 2H), 1.87-1.76 (m, 1H),1.76-1.54 (m, 3H), 1.47 (s, 3H), 1.45 (s, 3H) 29

1.40E− 05 2.58 16.39/ 31.91 Calculated: 370.1816, Found: 370.1823 δ7.37-7.28 (m, 1H), 6.96- 6.88 (m, 2H), 4.22 (dd, J = 8.0, 6.1 Hz, 1H),3.69-3.53 (m, 2H), 2.78 (t, J = 7.2 Hz, 2H), 1.89-1.76 (m, 1H),1.75-1.52 (m, 3H), 1.48 (s, 3H), 1.46 (s, 3H) 30

1.37E− 05 2.1 22.37/ 33.36 Calculated: 370.1816, Found: 370.1820 δ6.94-6.87 (m, 2H), 6.84- 6.77 (m, 1H), 4.19 (dd, J = 8.2, 6.1 Hz, 1H),3.67-3.49 (m, 2H), 2.72 (t, J = 7.2 Hz, 2H), 1.85-1.49 (m, 4H), 1.47 (s,3H), 1.44 (s, 3H) 31

2.06E− 06 0.596 18.61/ 33.53 Calculated: 370.1816, Found: 370.1823 δ7.31 (tt, J = 8.6, 6.6 Hz, 1H), 7.05-6.79 (m, 2H), 4.21 (dd, J = 8.3,6.0 Hz, 1H), 3.74-3.61 (m, 2H), 2.72 (t, 7.2 Hz, 2H), 1.85-1.50 (m, 4H),1.48 (s, 3H), 1.45 (s, 3H) 32

No Binding 28.33 27.33/ 48.42 Calculated: 388.1722, Found: 388.1724 δ7.17-6.96 (m, 2H), 4.18 (dd, J = 8.2, 6.2 Hz, 1H), 3.58-3.50 (m, 2H),2.72 (t, J = 7.1 Hz, 2H), 1.85-1.49 (m, 4H), 1.48 (s, 3H), 1.45 (s, 3H)33

4.50E− 05 0.06 17.96/ 26.94 Calculated: 388.1722, Found: 388.1722 δ6.96-6.72 (m, 2H), 4.20 (dd, J = 8.3, 6.0 Hz, 1H), 3.71-3.58 (m, 2H),2.72 (t, J = 7.1 Hz, 2H), 1.74-1.49 (m, 4H), 1.48 (s, 3H), 1.45 (s, 3H)34

5.20E− 05 3.48 19.76/ 39.5 Calculated: 335.1957, Found: 335.1961 δ8.48-8.39 (m, 2H), 7.37 (ddd, J = 4.5, 1.6, 0.8 Hz, 2H), 4.23 (dd, J =7.7, 6.1 Hz, 1H), 3.72-3.58 (m, 2H), 2.85 (t, J = 7.4 Hz, 2H), 1.92-1.57(m, 4H), 1.47 (s, 3H), 1.45 (s, 3H) 35

5.40E− 05 0.59 45.16/ 55.81 m/z = 375.15 [M + H]⁺ δ 8.29 (s, 1H),7.40-7.30 (m, 2H), 7.05 (t, J = 6.9 Hz, 2H), 6.95 (s, 1H), 4.91-4.49 (m,1H), 3.63 (s, 2H), 2.75- 2.71 (m, 2H), 2.13 (s, 3H), 2.01-1.92 (m, 1H),1.81- 1.70 (m, 1H), 1.65-1.56 (m, 2H). 36

No Binding 1.69 56.84/ 77.31 m/z = 357.35 [M + H]⁺ δ 8.29 (s, 1H),7.36-7.22 (m, 5H), 6.95 (s, 1H), 4.89-4.49 (m, 1H), 3.64 (s, 2H), 2.72-2.68 (m, 2H), 2.13 (s, 3H), 1.98-1.91 (m, 1H), 1.82-1.70 (m, 1H),1.63-1.51 (m, 2H). 37

2.10E− 05 23.83 25.46/ 58.20 m/z = 381.2 [M + H]⁺ δ 7.34-7.29 (m, 2H),7.06- 7.00 (m, 2H), 4.28 (t, J = 6.3 Hz, 1H), 3.55 (s, 2H), 3.12 (t, J =6.6 Hz, 2H), 2.84 (s, 6H), 1.87-1.68 (m, 4H), 1.47 (s, 3H), 1.45 (s,3H). 38

5.32E− 07 19.19 28.44/ 33.98 m/z = 376.25 [M + H]⁺ δ 8.55 (s, 1H),7.71-7.63 (m, 1H), 7.62-7.60 (m, 1H), 7.44-7.37 (m, 2H), 4.85 (s, 2H),4.38-4.35 (m, 1H), 2.98 (t, J = 7.2 Hz, 2H), 1.96- 1.87 (m, 1H),1.84-1.73 (m, 3H), 1.52 (s, 3H), 1.50 (s, 3H). 39

3.96E− 05 10.33 27.98/ 37.66 m/z = 352.15 [M + H]⁺ δ 7.32-7.27 (m, 2H),7.06- 6.96 (m, 2H), 4.15-4.10 (m, 1H), 3.53 (s, 2H), 1.83-1.23 (m, 12H),0.96-0.85 (m, 3H). 40

5.53E− 05 0.07 19.98/ 37.37 m/z = 392.25 [M + H]⁺ δ 8.54 (s, 1H), 7.96(t, J = 6.9 Hz, 2H), 7.53-7.40 (m, 2H), 4.86 (s, 2H), 4.33 (t, J = 6.0Hz, 1H), 2.95 (t, J = 7.1 Hz, 2H), 1.91-1.74 (m, 4H), 1.50 (s, 3H), 1.48(s, 3H) 41

2.03E− 05 44.73 27.69/ 72.75 m/z = 367.2 [M + H]⁺ δ 7.33-7.29 (m, 2H),7.06- 7.01 (m, 2H), 4.24-4.19 (m, 1H), 3.56 (s, 2H), 2.37-2.26 (m, 2H),2.13-1.93 (m, 2H), 1.48 (s, 3H), 1.46 (s, 3H). 42

2.20E− 04 12.06 21.07/ 30.16 Calculated: 402.1879, Found: 402.1880 δ7.61-7.57 (m, 2H), 7.50- 7.45 (m, 2H), 4.24-4.14 (m, 1H), 3.66 (s, 2H),2.72 (t, J = 7.1 Hz, 2H), 1.86-1.49 (m, 4H), 1.46 (s, 3H), 1.43 (s, 3H).43

Pending Pending Pending m/z = 392.15 [M + H]⁺ δ 7.97 (t, J = 6.9 Hz,2H), 7.53-7.39 (m, 2H), 4.87 (s, 2H), 4.25 (t, J = 7.8 Hz, 1H), 2.75 (t,J = 14.1 Hz, 2H), 1.85-1.46 (m, 10H). 44

Pending Pending Pending m/z = 353.15 [M + H]⁺ δ 7.34-7.29 (m, 2H), 7.07-7.02 (m, 2H), 4.24 (q, J = 6.0 Hz, 1H), 3.56 (s, 2H), 2.80 (t, J = 7.2Hz, 2H), 1.91-1.44 (m, 10H). 45

Pending Pending Pending m/z = 389.20 [M + H]⁺ δ 7.11-7.05 (m, 2H), 4.21(dd, J = 6.0, 4.5 Hz, 1H), 3.56-3.52 (m, 2H), 2.77 (t, J = 5.4 Hz, 2H),1.85-1.45 (m, 10H). 46

Pending Pending Pending m/z = 415.15 [M + H]⁺ δ 7.36- 7.28 (m, 4H),7.22- 7.18 (m, 2H), 7.02-6.96 (m, 2H), 4.51-4.46 (m, 1H), 4.07 (s, 2H),3.47 (s, 2H), 3.14-2.90 (m, 2H), 1.36 (d, J = 5.4 Hz, 6H).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. A compound having a structure represented by a formula:

wherein n is 0 or 1; wherein each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, halogen, and C₁-C₄ alkyl; orwherein each of R^(1a) and R^(1b), when present, are covalently bondedand, together with the intermediate atoms, comprise an unsubstitutedcyclopropyl group; wherein each of R² and R⁴ is independently selectedfrom hydrogen and C₁-C₄ alkyl; wherein R³ is selected from —(C₁-C₈alkyl)NR^(10a)R^(10b), —(C₁-C₈ alkyl)C(O)NR^(10a)R^(10b), C₂-C₈ alkyl,and —(C₁-C₄)Ar²; wherein each of R^(10a) and R^(10b) is independentlyselected from hydrogen and C₁-C₄ alkyl; wherein Ar² is C₆ arylpara-substituted with a —(CH₂)_(m)NR^(20a)R^(20b) group, and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; wherein mis 1, 2, 3, or 4; and wherein each of R^(20a) and R^(20b) isindependently selected from hydrogen and C₁-C₄ alkyl; wherein each ofR^(5a) and R^(5b) is hydrogen; or wherein each of R^(5a) and R^(5b) isindependently C₁-C₄ alkyl; or wherein each of R^(5a) and R^(5b) arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted C₃-C₆ group; and wherein R⁶ is hydrogen; or wherein eachof R^(5a) and R^(5b) together are covalently bonded to R⁶ and, togetherwith the intermediate atoms, comprise a C₃-C₅ heteroaryl groupsubstituted 0, 1, 2, or 3 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl; andwherein Ar¹ is selected from aryl and heteroaryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CN,—NH₂, —OH, —NO₂, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄cyanoalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄alkylamino, (C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, or apharmaceutically acceptable salt thereof, provided that when each ofR^(5a) and R^(5b) is hydrogen, then R³ is not C₂-C₈ alkyl, and providedthat when n is 0, then each of R^(5a) and R^(5b) is independently C₁-C₄alkyl or each of R^(5a) and R^(5b) are covalently bonded and, togetherwith the intermediate atoms, comprise an unsubstituted C₃-C₆ group, andR⁶ is hydrogen.
 2. The compound of claim 1, wherein n is
 0. 3. Thecompound of claim 1, wherein n is
 1. 4. The compound of claim 1, whereineach of R^(1a) and R^(1b), when present, is hydrogen, wherein each ofR^(1a) and R^(1b), when present, are covalently bonded and, togetherwith the intermediate atoms, comprise an unsubstituted cyclopropylgroup. 5-9. (canceled)
 10. The compound of claim 1, wherein each of R²and R⁴ is hydrogen.
 11. The compound of claim 1, wherein R³ is —(C₁-C₈alkyl)Nr^(10a)R^(10b). 12-14. (canceled)
 15. The compound of claim 1,wherein R³ is C₂-C₈ alkyl.
 16. (canceled)
 17. The compound of claim 1,wherein R³ is —(C₁-C₄)Ar². 18-28. (canceled)
 29. The compound of claim1, wherein the compound has a structure represented by a formula:


30. The compound of claim 1, wherein the compound has a structurerepresented by a formula:


31. The compound of claim 1, wherein the compound has a structurerepresented by a formula:

32-36. (canceled)
 37. The compound of claim 1, wherein the compound hasa structure represented by a formula:


38. The compound of claim 1, wherein the compound has a structurerepresented by a formula:

wherein each of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) areindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ cyanoalkyl, C₁-C₄hydroxyalkyl, C₁-C₄ haloalkoxy, C₁-C₄ alkoxy, C₁-C₄ alkylamino,(C₁-C₄)(C₁-C₄) dialkylamino, and C₁-C₄ aminoalkyl, provided that atleast two of R^(21a), R^(21b), R^(21c), R^(21d), and R^(21e) arehydrogen. 39-43. (canceled)
 44. The compound of claim 1, wherein thecompound has a structure represented by a formula:


45. (canceled)
 46. The compound of claim 1, wherein the compound isselected from:


47. A pharmaceutical composition comprising an effective amount of thecompound of claim 1, and a pharmaceutically acceptable carrier.
 48. Amethod for treating a disorder of uncontrolled cellular proliferation ina subject, the method comprising administering to the subject aneffective amount of the compound of claim 1, thereby treating thedisorder. 49-54. (canceled)
 55. The method of claim 48, wherein thedisorder is a cancer.
 56. The method of claim 55, wherein the cancer isselected from a sarcoma, a carcinoma, a hematological cancer, a solidtumor, breast cancer, cervical cancer, gastrointestinal cancer,colorectal cancer, brain cancer, skin cancer, prostate cancer, ovariancancer, thyroid cancer, testicular cancer, pancreatic cancer, livercancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma,chronic myeloproliferative disorder, myelodysplastic syndrome,myeloproliferative neoplasm, non-small cell lung carcinoma, and plasmacell neoplasm (myeloma).
 57. The method of claim 55, wherein the canceris a solid tumor. 58-82. (canceled)